Gut Commentary

NLRP6 deficiency enhances macrophage-mediated phagocytosis via E-Syt1 to inhibit hepatocellular carcinoma progression

Gougelet, A. — 2026-06-09T03:23:36-07:00

This last decade, immunotherapies have shaken up cancer treatment, but only a small percentage of patients benefit from current regimens targeting immune checkpoint inhibitors, including in hepatocellular carcinoma (HCC).1 Genetic and epigenetic intratumour heterogeneity, as well as diversity of immune cell infiltrates, significantly impacts tumour response to targeted therapies. In particular, tumour-associated macrophages (TAM), major components of the immune cell infiltrate, are strongly versatile immune cells. They acquire a large diversity of phenotypes according to cellular and non-cellular signals arising in the tumour niche.2 An ambivalent role is played by TAM during cancer development: they can either favour tumourigenesis and invasion through immunosuppressive and proangiogenic activities or can help suppress tumour growth by their robust phagocytic and immunopotentiation capabilities. Therefore, redirecting macrophage functions towards tumouricidal activities emerges as an interesting strategy to combat solid tumours.3 A range of strategies are used to exploit...

SIRT6-GLUL axis: rewiring nitrogen metabolism in intrahepatic cholangiocarcinoma

Zhou, H., Li, H., Wu, N., Calvisi, D. F. — 2026-06-09T03:23:36-07:00

Intrahepatic cholangiocarcinoma (ICC) is a highly lethal primary liver tumour for which systemic therapies offer limited survival benefit.1–3 Over the past few decades, several signalling pathways associated with ICC development and progression have been identified. These molecular cascades affect the various characteristics of malignant cholangiocytes, including proliferation, survival, invasion, metastasis and metabolism.1–5 Thus, delineation of these pathways and their crosstalk may aid tailoring innovative therapies for this challenging disease.

Although metabolic rewiring is a defining feature of ICC, most work has centred on glucose and lipid pathways to date.1 2 In Gut, Zhang etal reported nitrogen metabolism at the forefront by showing that the chromatin regulator Sirtuin6 (SIRT6; a NAD⁺ dependent deacetylase) can act as an oncogenic driver in ICC through transcriptional and post-translational upregulation of glutamine synthetase (GLUL;...

Multiomics- and artificial intelligence-powered research platforms for enhancing understanding and prediction of the cholangiocarcinoma patient journey

Corrales, F., Cardinale, V. — 2026-06-09T03:23:36-07:00

The main purposes of research in cholangiocarcinoma (CCA) are prevention, early diagnosis and the development of effective therapies tailored to each patient’s clinical course and general condition.1 This holistic vision is integral to the framework of P5 Medicine (personalised, predictive, preventive, participatory and population-based) and aligns with the modern principles of translational and precision medicine.2 Within this framework, the traditional notion of diagnosis as a ‘box that contains’ must be re-examined in light of the true pathobiological determinants of both the patient and the disease.3 4 Accompanying this evolutionary journey in biomedicine is the concept of biomarkers, which many regard as the key enabler of P5 Medicine.

CCA still suffers from a lack of precision in both clinical and research approaches.3 4 The anatomical classification of biliary tract cancer (BTC), including CCA, gallbladder cancer and ampullary cancer,...

Post-infection disorders of the gut: of latitude and longitude

Gwee, K. A. — 2026-06-09T03:23:36-07:00

The study by Marasco et al, in Gut, was ambitious in its aim to employ an epidemiology survey to establish post-infection disorders of gut-brain interaction (PI-DGBI) as an entity distinct from other DGBIs.1 This, after all, was not a mechanistic study. However, if we take this study in conjunction with its mothership the Rome Foundation Global Epidemiology Study (RFGES) and her spawn, the data makes a compelling case for infection as a singular pathophysiology for DGBI.

The RFGES is a mammoth study recruiting at least 2000 subjects each from 33 countries worldwide. In the mothership study, that reported on the wider DGBI cohort, functional constipation (11.7%) was the most prevalent, followed by unspecified functional bowel disorders (8.8%), functional dyspepsia (FD) (7.1%), functional diarrhoea (4.7%), irritable bowel syndrome (IBS) (4.1%) and functional bloating (3.5%).2 Essentially, it reinforced the typical profile of a DGBI patient, that is,...